Growth factors such as vascular endothelial growth factor (VEGF) have been suggested to play a role in the development of long-term diabetic complications including both proliferative and non-proliferative diabetic retinopathy. VEGF is expressed by a number of cell types in the retina including Muller cells and retinal pigmented epithelial (RPE) cells. VEGF levels are elevated in vitreous body samples from five subjects with diabetic retinopathy. This proposal will focus on the mechanism of enhanced VEGF expression in diabetic retinopathy, with emphasis on RPE cells. Specifically, the objective of this study is to test the hypothesis that reactive endogenous aldehydes that are elevated in diabetes and their advanced Glycation Endproducts (AGE) up-regulate expression of VEGF in RPE cells through alterations of intracellular redox status. The proposed studies will focus on the ketoaldehyde methylglyoxal (MeG) and the alpha-beta unsaturated aldehyde 4- hydroxynonenal (4HNE) to test the hypothesis. We designate this the Aldehyde (Oxidative) Stress Model of Diabetic Complications. The Specific Aims are: 1) To demonstrate that MeG, 4HNE and their AGE can alter intracellular redox status, resulting in up-regulation of VEGF expression in RPE cells. 2) To elucidate the mechanisms by which MeG, 4HNE and their AGE alter expression of VEGF. 3) To evaluate anti-oxidant strategies for countering the effects of MeG, 4HNE and their AGE. The Aldehyde (Oxidative) Stress Model emphasizes the role of carbonyl compounds in addition to glucose in the etiology of diabetic retinopathy. It provides a testable model that connects hyperglycemia-> oxidative stress-> growth factors-> diabetic retinopathy.